| First Author | Ueda K | Year | 2021 |
| Journal | Cancer Cell | Volume | 39 |
| Issue | 4 | Pages | 529-547.e7 |
| PubMed ID | 33667384 | Mgi Jnum | J:305020 |
| Mgi Id | MGI:6694730 | Doi | 10.1016/j.ccell.2021.02.006 |
| Citation | Ueda K, et al. (2021) MDMX acts as a pervasive preleukemic-to-acute myeloid leukemia transition mechanism. Cancer Cell 39(4):529-547.e7 |
| abstractText | MDMX is overexpressed in the vast majority of patients with acute myeloid leukemia (AML). We report that MDMX overexpression increases preleukemic stem cell (pre-LSC) number and competitive advantage. Utilizing five newly generated murine models, we found that MDMX overexpression triggers progression of multiple chronic/asymptomatic preleukemic conditions to overt AML. Transcriptomic and proteomic studies revealed that MDMX overexpression exerts this function, unexpectedly, through activation of Wnt/beta-Catenin signaling in pre-LSCs. Mechanistically, MDMX binds CK1alpha and leads to accumulation of beta-Catenin in a p53-independent manner. Wnt/beta-Catenin inhibitors reverse MDMX-induced pre-LSC properties, and synergize with MDMX-p53 inhibitors. Wnt/beta-Catenin signaling correlates with MDMX expression in patients with preleukemic myelodysplastic syndromes and is associated with increased risk of progression to AML. Our work identifies MDMX overexpression as a pervasive preleukemic-to-AML transition mechanism in different genetically driven disease subtypes, and reveals Wnt/beta-Catenin as a non-canonical MDMX-driven pathway with therapeutic potential for progression prevention and cancer interception. |
